The major function of the adrenal gland is to regulate metabolism in the body so that an intermittent intake of food can be regulated to maintain a constant metabolite supply to the cells. This is accomplished by producing steroid hormones which can control the conversion of incoming nutrients, such as aminoacids, glucose and fats into storage depots from which they can thereafter be released or interchanged, allowing a continuous flow of optimum energy and growth factors to the cells.
The steroid hormones are divided mainly into three classes. The first is glucocorticoids (cortisol), also known as gluconeogenic or diabetogenic steriods, which can convert aminoacids into glucose for direct use or store the glucose as glycogen for later use. Cortisol can therefore have an anti-anabolic effect through the depletion of aminoacids needed for protein synthesis and a diabetogenic effect through the direct release of glucose from the glycogen store.
A glucocorticoid excess, resulting from an excess of the pituitary hormone, adrenal cortico-trophic hormone (ACTH), which controls cortisol production, causes Cushing's Syndrome, an uncommon disease. Intake of an excess amount of cortisol from pharmacological use of steroids can also cause Cushing's Syndrome or Cushingoid-like disorders (hypercorticosteroidism, or more briefly hypercorticoidism) which are progeric in that they resemble the symptoms of the diseases of aging, e.g. obesity, hypertension, diabetes, renal stones, osteoporosis, mental disorder, menstrual disturbance, susceptibility to infection and poor wound healing.
The second category of steroids is known as the adrenal androgens. Dehydroepiandrosterone (DHEA) is the principal representative of this category. The adrenal androgens which have an anabolic action are produced with puberty, reach a peak in early adulthood and then, beyond the age of 50, decline to very low levels. Secretion of ACTH, which also controls corticosteroid production, shows no such age related fluctuation.
The third category of adrenal steroids is the mineralocorticoids (aldosterone) which control the mineral balance of the body and is partially under ACTH control in that ACTH accelerates the conversion of cholesterol to all adrenal steroids.
When the body is subjected to stress, physical or mental, e.g. injury, cold, starvation or threats, real or imagined, ACTH stimulates the adrenal cortex to produce steroids in increased amounts in order to provide the body with resources necessary for response to the stress, storage or release of glucose when needed, lipid deposition or mobilization in order to maintain the energy equilibrium of the body under conditions where extra energy may be needed and/or starvation of the cells becomes a possibility.
Under normal conditions, ACTH stimulates the adrenals to secrete both cortisol and DHEA. In the aging individual, cortisol is stimulated but DHEA is not, thus resulting in relative hypercortisolism.
It is shown in the aforesaid related application that DHEA is useful in the treatment of diabetes in mutant mice and treatment of adult-onset diabetes in obese individuals. The genetic form of diabetes in mice is associated with hypercorticosteroidism. Hypercorticosteroid syndromes can occur as a result of excessive ACTH production due either to stress, hypofunction of the adrenal glands, pituitary tumors, ectopic ACTH production or administration of pharmacologic doses of cortisol. DHEA is also known to be useful as an anti-obesity agent in animals and humans. Yen et al, Prevention of Obesity in Avy/a Mice by Dehydroepiandrosterone, Lipids, 12(5), 409 (1977); Kritchevsky et al, Influence of Dehydroepiandrosterone (DHEA) Cholesterol Metabolism in Rats, Pharm. Res. Comm., 15, No. 9 (1983); Abrahamsson et al, Catabolic Effects and the Influence on Horomonal Variables under Treatment with Gynodian-Depot or Dehydroepiandrosterone (DHEA) Oenanthate, Maturitas, 3 (1981) 225-234.
DHEA is metabolized in the body. A major metabolite is etiocholanolone (5-.beta.-androstan-3-.alpha.-ol-17-one, (hereinafter referred to as .alpha.-ET) and in normal individuals it is excreted in amounts of about 0.5 mg/100 ml. .beta.-etiocholanolone (5-.beta.-androstan-3-.beta.-ol-17-one, hereinafter referred to as .beta.-ET), was reported to be a minor metabolite of DHEA although evidence for its presence was based upon unmeasured spots on chromatograph strips observed during measurements of etiocholanolone excretion. Even when large quantities of .beta.-ET are ingested, most of the recovered excretion product is in the form of .alpha.-ET, with less than 5% of .beta.-ET found. Kappas, et al, The Thermogenic Effect and Metabolite Fate of Etiocholanolone in Man, J. Clin. Endocrin. & Metab., 18, 1043-1055 (1958). It thus appears that the 3.beta.-hydroxy compound undergoes almost quantitative conversion to the 3-.alpha.-hydroxy compound suggesting that the 3-.beta.-ET is not a natural compound but may be an artifact of isolation.
To confirm that .beta.-ET is not of natural origin, we used an RIA method for .alpha.-ET which is far more sensitive than existing chromatographic techniques and found that the injection in man of 40 mg of .beta.-ET yielded a serum value for etiocholanolone equal to that obtained from 40 mg of injected etiocholanolone. The antiserum used had insiginficant cross-reactivity with unchanged .beta.-ET.
It is considered that variations in response between the .alpha. and .beta. compounds are due to differences in the concentration of etiocholanolone available in the serum as the conversion from .beta. to .alpha. takes place. The conversion time could also account for differences in sojurn time, excretion rate and bioavailability of the two compounds and therefore different interactions with receptors and responses of target organs.
While we have shown that both .alpha.- and .beta.-ET are effective in preventing hyperglycemia and excess fat accumulation, the rates at which these actions take place may be influenced by the bioavailability of one or another of the isomers; the .beta.-ET serving as a slow delivery system with more prolonged action and the .alpha.-ET as a more rapid but shorter-acting agent. In the diabetic animal, a more prolonged effect may be optimum whereas in the obese animal, a higher initial quantity of etiocholanalone may be desirable. Our results indicate that this is so; .alpha.-ET is more effective in the obese animal, while .beta.-ET is more effective than .alpha.-ET in the diabetic.
.alpha.-ET had been considered to be an inert end product whose sole fate was conjugation and excretion until it was shown that in its free (unconjugated) state, it had highly potent pyrogenic effects when injected intramuscularly in males, less potency in females and none in other species. No febrile reaction results when .alpha.-ET is administered intravenosly, or orally, or when .beta.-ET is administered by any route. Kappas, et al., Thermogenic Properties of Steroids, in Methods in Hormone Research, Dorfman Ed. Vol. 4, p. 1 (New York & London Academic Press) (1965).
The spectrum of biological significance for etiocholanolones has been extended to include the regulation of porphyrin and hemesynthesis in hepatic and erythroid cells. Granick et al., Steroid Control of Porphyrin and Hemebiosynthesis, A New Biological Function of Steroid Hormone Metabolites, Proc. Nat. Acad. Sci., 57:1463 (1967). .alpha.-ET as well as other non-pyrogenic 5-.beta. saturated steroids are also inducers of porphyrin synthesis. Wolff, et al., The Biological Properties of Etiocholanolone, Ann. Int. Med., 67, 1268-1295 (1967).
It has now been discovered that the administration of .alpha.-ET, .beta.-ET or mixtures thereof reproduce the effects of DHEA in preventing the development of hyperglycemia and diabetes possibly by antagonizing the effects of hypercorticoidism. It was also discovered that the effective therapeutic amounts of these compounds are considerably lower than the dosage of DHEA required for maximum effect in normalizing blood sugar and maintaining islet integrity. It has further been found that these compounds are superior anti-obesity agents compared to DHEA.
It is accordingly the object of this invention to provide a new method for treating obesity, diabetes-obesity syndrome and associated hypercorticoidism and enhancing the function or by preventing the destruction of the pancreatic islet beta cells using .alpha.-ET and/or .beta.-ET as anti-obesity antidiabetic and antihyperglycemic agents.